Tropane derivatives having dopamine reuptake inhibitor activity for the treatment of ischemic diseases

ABSTRACT

The present invention relates to the use of tropane derivatives having dopamine reuptake inhibitor activity for the treatment of diseases associated with reduced blood flow to the brain or with instances of a temporary break in blood supply to the brain, such as ischemic diseases.

TECHNICAL FIELD

The present invention relates to the use of tropane derivatives havingdopamine reuptake inhibitor activity for the treatment of diseasesassociated with reduced blood flow to the brain or with instances of atemporary break in blood supply to the brain, such as ischemic diseases.

BACKGROUND ART

Cerebral ischemia can result in varying degrees of tissue damage.Conditions of severe ischemia can produce irreversible injury, whereasin conditions of moderate ischemia, tissue damage may be reversible. Thereversibility of tissue damage—i.a. in the striatum—is important for thedevelopment of new therapeutic approaches for treatment.

In connection with an incidence of cerebral ischemia, an excessiveamount of glutamate is released from the cortex to the striatumresulting in an excessive depolarization of dopaminergic nerve terminalsprimarily mediated by sodium influx. This depolarization results in amassive efflux of dopamine, which in turn exerts a neurodegenerativeeffect in the striatum.

Compounds capable of reducing the striatal dopamine level in suchsituations would therefore be considered useful for the treatmenttreatment of diseases associated with reduced blood flow to the brain orwith instances of a temporary break in blood supply to the brain, suchas ischemic diseases.

It has been mentioned that dopamine release mediated by reversal of thedopamine transporter (DAT) may also be of importance in ischemicconditions in the striatum such that a part of the neurodegenerativechanges in the striatum following ischemia results from dopamine releasemediated by the dopamine transporter (Leviel V, NeurochemistryInternational, 38, 83-106, 2001).

DETAILED DISCLOSURE OF THE INVENTION

It has now been found that a tropane derivative having dopamine reuptakeinhibitor activity is useful in the treatment, prevention or alleviationof a disease associated with reduced blood flow to the brain or with aninstance of a temporary break in blood supply to the brain.

Thus, in a first aspect the invention provides the use of a tropanederivative having dopamine reuptake inhibitor activity or apharmaceutically acceptable salt thereof for the manufacture of amedicament for the treatment, prevention or alleviation of a diseaseassociated with reduced blood flow to the brain or with an instance of atemporary break in blood supply to the brain.

In a second aspect, the invention provides a method for the treatment,prevention or alleviation of a disease associated with reduced blood tothe brain or with an instance of a temporary break in blood supply tothe brain in a subject, comprising administering to said subject atherapeutically effective amount of a tropane derivative having dopaminereuptake inhibitor activity or a pharmaceutically acceptable saltthereof.

In one embodiment, the tropane derivative having dopamine reuptakeinhibitor activity is a compound of the general formula (I)

or a pharmaceutically acceptable addition salt thereof or the N-oxidethereof, wherein

-   -   R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkylalkyl or 2-hydroxyethyl;    -   R³ is        -   CH₂—X—R′,            -   wherein X is O, S, or NR″;            -   wherein R″ is hydrogen or alkyl; and            -   R′ is alkyl, alkenyl, alkynyl, cycloalkyl,                cycloalkylalkyl, or —CO-alkyl;        -   heteroaryl which may be substituted one or more times with            -   alkyl, cycloalkyl, or cycloalkylalkyl;            -   phenyl which may be substituted one or more times with                substituents selected from the group consisting of                halogen, CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl,amino,                nitro, and heteroaryl;            -   phenylphenyl;            -   pyridyl which may be substituted one or more times with                substituents selected from the group consisting of                halogen, CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl,                amino, nitro, and heteroaryl;            -   thienyl which may be substituted one or more times with                substituents selected from the group consisting of                halogen, CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl,                amino, nitro, and heteroaryl; or            -   benzyl which may be substituted one or more times with                substituents selected from the group consisting of                halogen, CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl,                amino, nitro, and heteroaryl; or        -   (CH₂)_(n)CO₂R¹¹, COR¹¹, or CH₂R¹²;            -   wherein R¹¹ is                -   alkyl, cycloalkyl, or cycloalkylalkyl;                -   phenyl which may be substituted one or more times                    with substituents selected from the group consisting                    of halogen, CF₃, CN, alkoxy, alkyl, alkenyl,                    alkynyl, amino, nitro, and heteroaryl;                -   phenylphenyl;                -   pyridyl which may be substituted one or more times                    with substituents selected from the group consisting                    of halogen, CF₃, CN, alkoxy, alkyl, alkenyl,                    alkynyl, amino, nitro, and heteroaryl;                -   thienyl which may be substituted one or more times                    with substituents selected from the group consisting                    of halogen, CF₃, CN, alkoxy, alkyl, alkenyl,                    alkynyl, amino, nitro, and heteroaryl; or                -   benzyl;            -   n is 0 or 1; and            -   R¹² is                -   O-phenyl which may be substituted one or more times                    with substituents selected from the group consisting                    of halogen, CF₃, CN, alkoxy, alkyl, alkenyl,                    alkynyl, amino, nitro, and heteroaryl; or                -   O—CO-phenyl which may be substituted one or more                    times with substituents selected from the group                    consisting of halogen, CF₃, CN, alkoxy, alkyl,                    alkenyl, alkynyl, amino, nitro, and heteroaryl; or        -   CH═NOR′;            -   wherein R′ is                -   hydrogen;                -   alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl                    or aryl; all of which may be substituted with                -    —COOH;                -    —COO-alkyl;                -    —COO-cycloalkyl; or                -    phenyl which may be substituted one or more times                    with substituents selected from the group consisting                    of halogen, CF₃, CN, alkyl, cycloalkyl, alkoxy,                    cycloalkoxy, alkenyl, alkynyl, amino, and nitro;    -   R⁴ is        -   3,4-methylenedioxyphenyl or        -   phenyl, benzyl, naphthyl, or heteroaryl all of which may be            substituted one or more times with substituents selected            from the group consisting of halogen, CF₃, CN, alkoxy,            cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino,            nitro, and heteroaryl.

In a special embodiment of the compound of general formula I, R³ is

-   -   1,2,4-oxadiazol-3-yl which may by substituted in the 5 position        with        -   alkyl, cycloalkyl, or cycloalkylalkyl;        -   phenyl which may be substituted one or more times with            substituents selected from the group consisting of halogen,            CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and            heteroaryl;        -   phenylphenyl; or        -   benzyl which may be substituted one or more times with            substituents selected from the group consisting of halogen,            CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and            heteroaryl; or    -   1,2,4-oxadiazol-5-yl which may by substituted in the 3 position        with        -   alkyl, cycloalkyl, or cycloalkylalkyl;        -   phenyl which may be substituted one or more times with            substituents selected from the group consisting of halogen,            CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and            heteroaryl;        -   phenylphenyl;        -   benzyl which may be substituted one or more times with            substituents selected from the group consisting of halogen,            CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and            heteroaryl;        -   pyridyl which may be substituted one or more times with            substituents selected from the group consisting of halogen ,            CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro and            heteroaryl; or        -   thienyl which may be substituted one or more times with            substituents selected from the group consisting of halogen,            CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro and            heteroaryl.

In a further special embodiment of the compound of general formula I, R³is

-   -   CH₂—X—R′,        -   wherein X is O, S, or NR″;        -   wherein R″ is hydrogen or alkyl; and        -   R′ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,            or —CO-alkyl.

In a still further embodiment of the compound of general formula I, R3is

-   -   CH═NOR′;        -   wherein R′ is            -   hydrogen;            -   alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl or                aryl; all of which may be substituted with                -   —COOH;                -   —COO-alkyl;                -   —COO-cycloalkyl; or                -   phenyl which may be substituted one or more times                    with substituents selected from the group consisting                    of halogen, CF₃, CN, alkyl, cycloalkyl, alkoxy,                    cycloalkoxy, alkenyl, alkynyl, amino, and nitro.

In a further special embodiment of the compound of general formula I, R⁴is phenyl, which is substituted once or twice with substituents selectedfrom the group consisting of halogen, CF₃, CN, alkoxy, cycloalkoxy,alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl.

In a more special embodiment, R⁴ is phenyl substituted once or twicewith chlorine.

In a further special embodiment, the tropane derivative having dopaminereuptake inhibitor activity is a (1R,2R,3S)-2,3-disubstitutedtropane-derivative of formula I.

In a still further embodiment, the tropane derivative having dopaminereuptake inhibitory activity is a compound of general formula I wherein

-   -   R³ is        -   —CH₂—X—R′, wherein X is O or S, and R′ is methyl, ethyl,            propyl, or cyclopropylmethyl;        -   CH═NOR′;            -   wherein R′ is hydrogen or alkyl, or        -   1,2,4-oxadiazol-5-yl which may by substituted in the 3            position with alkyl.

In a still further embodiment, the tropane derivative having dopaminereuptake inhibitory activity is a compound of general formula I whereinR is hydrogen, methyl, ethyl or propyl.

In a still further embodiment, the tropane derivative having dopaminereuptake inhibitory activity is a compound of general formula I whereinR⁴ is 3,4-dichlorophenyl.

In a special embodiment, the tropane derivative having dopamine reuptakeinhibitor activity is a compound of the general formula (I) selectedfrom:

-   -   (1R,2R,3S)-2-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-3-(4-fluorophenyl)tropane;    -   (1R,2R,3S)-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)-3-(4-fluorophenyl)tropane;    -   (1R,2R,3S)-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)-3-(4-methylphenyl)-tropane;    -   (1R,2R,3S)-2-(3-Benzyl-1,2,4-oxadiazol-5-yl)-3-(4-fluorophenyl)tropane;    -   (1R,2R,3S)-2-(3-(4-Phenyl-phenyl)-1,2,4-oxadiazol-5-yl)-3-(4-fluorophenyl)tropane;    -   (1R,2R,3S)-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)-3-(2-naphthyl)tropane;    -   (1R,2R,3S)-3-(3,4-Dichlorophenyl)tropane-2-aldoxime;    -   (1R,2R,3S)-3-(3,4-Dichlorophenyl)-tropane-2-O-methyl-aldoxime;    -   (1R,2R,3S)-3-(3,4-Dichlorophenyl)tropane-2-O-benzyl-aldoxime;    -   (1R,2R,3S)-3-(3,4-Dichlorophenyl)tropane-2-O-ethoxycarbonylmethyl-aldoxime;    -   (1R,2R,3S)-3-(3,4-Dichlorophenyl)tropane-2-O-methoxycarbonylmethyl-aldoxime;    -   (1R,2R,3S)-3-(3,4-Dichlorophenyl)tropane-2-O-(1-ethoxycarbonyl-1,1-dimethyl-methyl)-aldoxime;    -   (1R,2R,3S)-3-(3,4-Dichlorophenyl)tropane-2-O-carboxymethyl-2-aldoxime;    -   (1R,2R,3S)—N-Normethyl-3-(3,4-dichlorophenyl)tropane-2-O-methyl-aldoxime;    -   (1R,2R,3S)—N-Normethyl-3-(3,4-dichlorophenyl)tropane-2-O-benzyl-aldoxime;    -   (1R,2R,3S)-3-(4-Methylphenyl)tropane-2-O-methyl-aldoxime;    -   (1R,2R,3S)-3-(3,4-Dichlorophenyl)tropane-2-O-(1,1-dimethylethyl)-aldoxime;    -   (1R,2R,3S)-3-(4-Chlorophenyl)tropane-2-O-aldoxime;    -   (1R,2R,3S)-3-(4-Chlorophenyl)tropane-2-O-methylaldoxime        hydrochloride;    -   (1R,2R,3S)-3-(4-Chlorophenyl)tropane-2-O-methoxycarbonylmethyl-aldoxime;    -   (1R,2R,3S)-3-(3,4-Dichlorophenyl)tropane-2-O-(2-propynyl)-aldoxime;    -   (1R,2R,3S)-3-(3,4-Dichlorophenyl)tropane-2-O-(2-methylpropyl)-aldoxime;    -   (1R,2R,3S)-3-(3,4-Dichlorophenyl)tropane-2-O-cyclopropylmethyl-aldoxime;    -   (1R,2R,3S)-3-(3,4-Dichlorophenyl)tropane-2-O-ethyl-aldoxime;    -   (1R,2R,3S)-2-Methoxymethyl-3-(3,4-dichlorophenyl)-tropane;    -   (1R,2R,3S)-2-Isopropoxymethyl-3-(3,4-dichlorophenyl)-tropane;    -   (1R,2R,3S)-2-Ethoxymethyl-3-(3,4-dichlorophenyl)-tropane;    -   (1R,2R,3S)-2-Cyclopropylmethyloxymethyl-3-(3,4-dichlorophenyl)-tropane;    -   (1R,2R,3S)-2-Methoxymethyl-3-(4-chlorophenyl)-tropane;    -   (1R,2R,3S)—N-Normethyl-2-methoxymethyl-3-(4-chlorophenyl)-tropane;    -   (1R,2R,3S)-2-Ethoxymethyl-3-(4-chlorophenyl)-tropane;    -   (1R,2R,3S)—N-Normethyl-2-methoxymethyl-3-(3,4-dichlorophenyl)-tropane;    -   (1R,2R,3S)—N-Normethyl-2-ethoxymethyl-3-(3,4-dichlorophenyl)-tropane;    -   (1R,2R,3S)—N-Normethyl-2-ethoxymethyl-3-(4-chlorophenyl)-tropane;    -   (1R,2R,3S)—N-Normethyl-2-cyclopropylmethyloxymethyl-3-(4-chlorophenyl)-tropane;    -   (1R,2R,3S)-2-Cyclopropylmethyloxymethyl-3-(4-chlorophenyl)-tropane;    -   (1R,2R,3S)-2-Ethylthiomethyl-3-(3,4-dichlorophenyl)-tropane;    -   (1R,2R,3S)-2-Hydroxymethyl-3-(4-fluorophenyl)tropane;    -   (1R,2R,3S)-2-Hydroxymethyl-3-(3,4-dichlorophenyl)tropane;    -   (1R,2R,3S)—N-Normethyl-N-(tert-butoxycarbonyl)-2-hydroxymethyl-3-(3,4-dichlorophenyl)tropane;    -   (1R,2R,3S)-2-Hydroxymethyl-3-(4-chlorophenyl)tropane;    -   (1R,2R,3S)-2-(3-(2-Furanyl)-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane;    -   (1R,2R,3S)-2-(3-(3-Pyridyl)-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane    -   (1R,2R,3S)—N-Normethyl-N-allyl-2-(3-(4-pyridyl)-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane;    -   (1R,2R,3S)—N-Normethyl-N-ethyl-2-(3-(4-pyridyl)-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane;    -   (1R,2R,3S)—N-Normethyl-N-(2-hydroxyethyl)-2-(3-(4-pyridyl)-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane;    -   (1R,2R,3S)—N-Normethyl-2-(3-(4-pyridyl)-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane;    -   (1R,2R,3S)—N-Normethyl-N-allyl-2-(3-(3-pyridyl)-1,2,4-oxadiazol-5-yl)-3-(3,4-dichilorophenyl)-tropane;    -   (1R,2R,3S)—N-Normethyl-N-allyl-2-(3-(2-pyridyl)-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane;    -   (1R,2R,3S)-2-(3-(2-Thienyl)-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)-tropane;    -   (1R,2R,3S)-2-(3-(2-Thienyl)-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane;    -   (1R,2R,3S)-2-(3-(4-Pyridyl)-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane;    -   (1R,2R,3S)-2-(3-(2-Pyridyl)-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane;    -   (1R,2R,3S)-2-(3-(4-Pyridyl)-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)-tropane;    -   (1R,2R,3S)-2-(3-(3-Pyridyl)-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)-tropane;    -   (1R,2R,3S)-2-(3-(2-Pyridyl)-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)-tropane;    -   (1R,2R,3S)-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)-3-(4-fluorophenyl)-tropane;    -   (1R,2R,3S)-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)-3-(4-methylphenyl)-tropane;    -   (1R,2R,3S)-2-(3-Benzyl-1,2,4-oxadiazol-5-yl)-3-(4-fluorophenyl)-tropane;    -   (1R,2R,3S)-2-(3-(4-Phenylphenyl)-1,2,4-oxadiazol-5-yl)-3-(4-fluorophenyl)-tropane;    -   (1R,2R,3S)-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)-3-(2-naphthyl)-tropane;    -   (1R,2R,3S)-2-(4-Chlorophenoxy-methyl)-3-(4-fluorophenyl)-tropane;    -   (1R,2R,3S)-2-(4-Chlorophenoxy-methyl)-3-(4-fluorophenyl)-tropane;    -   (1R,2R,3S)-2-(4-Chlorophenoxy-methyl)-3-(3,4-dichlorophenyl)-tropane;    -   (1R,2R,3S)-2-(4-Chlorophenoxy-methyl)-3-(4-methylphenyl)-tropane;    -   (1R,2R,3S)-2-(4-Benzoyloxy-methyl)-3-(4-fluorophenyl)-tropane;    -   (1R,2R,3S)-2-Carbomethoxy-3-(2-naphthyl)-tropane;    -   (1R,2R,3S)-2-Carbomethoxy-3-(3,4-dichlorophenyl)-tropane;    -   (1R,2R,3S)-2-Carbomethoxy-3-benzyl-tropane;    -   (1R,2R,3S)-2-Carbomethoxy-3-(4-chlorophenyl)-tropane;    -   (1R,2R,3S)-2-Carbomethoxy-3-(4-methylphenyl)-tropane;    -   (1R,2R,3S)-2-Carbomethoxy-3-(1-naphthyl)-tropane;    -   (1R,2R,3S)-2-Carbomethoxy-3-(4-phenylphenyl)-tropane;    -   (1R,2R,3S)-2-Carbomethoxy-3-(4-t-butyl-phenyl)-tropane;    -   (1R,2R,3S)-2-(4-Fluoro-benzoyl)-3-(4-fluorophenyl)-tropane;    -   or a pharmaceutically acceptable addition salt thereof.

In one embodiment, the tropane derivative having dopamine reuptakeinhibitor activity is a compound of the general formula (II)

or any of its enantiomers or any mixture thereof, a pharmaceuticallyacceptable addition salt thereof or the N-oxide thereofwherein

-   -   X and Y together forms ═O, ═S, ═NOR², ═CR³R⁴, ═N—CN, ═N—NR⁷R⁸,        —(CH₂)_(m)—, or —W′—(CH₂)_(p)—W″—, or one of X and Y is hydrogen        and the other is —OR⁵, —SR⁵, or —NR⁵R⁶ Z is hydrogen, —COOR⁹;    -   R³ and R⁴ are independently hydrogen, halogen, alkyl,        cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy, aryl,        arylalkyl, or —(CH₂)_(q)—COOR²;    -   R², R⁵ and R⁶ are independently hydrogen, alkyl, cycloalkyl,        cycloalkylalkyl, alkenyl, alkynyl, aryl, or arylalkyl,        —CO-alkyl, or —SO₂-alkyl;    -   R⁷ and R⁸ are independently hydrogen, alkyl, cycloalkyl,        cycloalkylalkyl, alkenyl, alkynyl, aryl, or arylalkyl;    -   R⁹ is alkyl, alkenyl or alkynyl;    -   R¹ is alkyl, alkenyl, alkynyl, aryl, or arylalkyl;    -   where said aryl groups may be substituted one or more times with        substituents selected from the group consisting of halogen, CF₃,        CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl,        amino, alkylamino, dialkylamino and nitro;    -   W′ and W″ are each independently O or S;    -   n is 1, 2, 3, or 4;    -   m is 2, 3, 4,or 5;    -   p is 1, 2, 3, 4, or 5; and    -   q is 0, 1, 2, 3, or 4.

In a special embodiment, the tropane derivative having dopamine reuptakeinhibitor activity is a compound of the general formula (II) selectedfrom:

-   -   (1S,2S,4S,7R)-2-(3,4-Dichlorophenyl)-8-azatricyclo[5.4.0.0^(4,8)]undecan-11-one;    -   (1S,2S,4S,7R)-2-(3,4-Dichlorophenyl)-8-azatricyclo[5.4.0.0^(4,8)]undecan-11-ol;    -   (1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]decan-5-one;    -   (1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]decan-5-one        O-methyl-oxime;    -   (1S,2S,4S,7R)-2-(4-Chlorophenyl)-8-azatricyclo[5.4.0.0^(4,8)]undecan-11-one;    -   (1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-7-aza-tricyclo[5.3.0.0^(4,8)]decan-5-ol;    -   (1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]dec-5-yl        acetate;    -   (1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]dec-5-yl        methane sulphate;    -   (1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-5-methoxy-7-azatricyclo[5.3.0.0^(4,8)]decane;    -   (1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-5-ethoxy-7-azatricyclo[5.3.0.0^(4,8)]decane;    -   (1S,3S,4S,8R)-3-(4-Chlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]decan-5-one;    -   (1S,3S,4S,8R)-3-(4-Chlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]decan-5-ol;    -   (1S,3S,4S,8R)-3-(4-Chlorophenyl)-5-ethoxy-7-azatricyclo[5.3.0.0^(4,8)]decane;    -   (1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]decan-5-one        O-bensyl-oxime;    -   (1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]decan-5-one        O-allyl-oxime;    -   (1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]decan-5-one        oxime;    -   (1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]decan-5-one        O-tert.-butyl-oxime;    -   (1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]decan-5-one        O-ethyl-oxime;    -   (1S,3S,4S,8R)-5-Allyloxy-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]decane;    -   Ethyl        (1S,3S,4S,8R)-2-[3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]dec-5-yliden]acetate;    -   (1S,3S,4S,8R)-3-(4-Chlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]decan-5-one        oxime;    -   N1-[1S,3S,4S,8R)-3-(4-Chlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]dec-5-yl]acetamide;    -   (1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]dec-5-yl        amine;    -   or a pharmaceutically acceptable addition salt thereof.

In one further embodiment, the disease to be treated, prevented oralleviated is selected from ischemic diseases, anoxic episodes, andinjury to the brain and other parts of the CNS caused by trauma or otherinjury, for example a blow to the head. In such reduced blood flowepisodes, or episodes where there is a temporary break in blood supply,oxygen supply to the brain is reduced or interrupted.

In a further embodiment, the disease to be treated, prevented oralleviated is selected from cerebrovascular disorders such as cerebralischemia or cerebral infarction resulting from a range of conditions,such as tromboembolic or haemorrhagic stroke, cerebral vasospasm,hypoglycaemia, cardiac arrest, perinatal asphyxia, anoxia such as fromnear-drowning, pulmonary surgery and cerebral trauma.

The method can be used in the treatment or prevention of traumatic braininjury, in particular ischemic, hypoxic or anoxic brain damage, spinalcord injury, tissue ischemia and reperfusion injury in a mammal at riskfor such damage.

The brain damage may brain damage may follow or be caused by: cerebralischemia, cardiac arrest, high-risk surgery such as cardiac surgery,stroke, neonatal hypoxia, hypoxia caused by compromised lung function,neonatal anoxia, anoxia caused by compromised lung function, cerebraltrauma, secondary regional ischemia induced by brain oedema, increasedintercranial pressure, open brain surgery, endarterectomy, surgicalinterventions involving temporary, artificially sustained arrest ofcardiopulmonary functions resulting in impairment of cerebral bloodflow, and emergency treatment involving cardiopulmonary resuscitation(CPR).

In a special embodiment, the disease to be treated, prevented oralleviated is acute treatment of ischemic stroke, treatment of braindamage following global cerebral ischemia, or prevention of brain damagefollowing high risk surgery.

In many instances of brain ischemia, treatment is not available to thepatient for several, e.g. up to 6 hours, in stroke patients typically 3to 6 hours, after the ischemic injury. Such a delay places great demandson any therapeutic regime designed to mitigate ischemic brain injury. Ithas been found, however, that the tropane derivative having dopaminereuptake inhibitor activity for use according to the invention issurprisingly effective whether administered pre-ischemically orpost-ischemically.

When administered post-ischemically it is advisable that the tropanederivative having dopamine reuptake inhibitor activity be administeredwithin one day of the ischemic insult. Although the tropane derivativehaving dopamine reuptake inhibitor activity used in the invention may beadministered as late as 14 hours after brain reperfusion, the treatmentshould preferably be carried out within 12 hours of ischemic alleviationor reperfusion. Preferably, the treatment should occur within 6 hours ofalleviation of ischemia. Yet more preferred is the administration of thetropane derivative having dopamine reuptake inhibitor activity used inthe invention within 3 hours of alleviation of ischemia

As used herein, CNS includes the brain and spinal cord and combatingincludes both therapy and diagnosis.

Tropane Derivatives having Dopamine Reuptake Inhibitor Activity

The potential of a given substance to act as a dopamine reuptakeinhibitors activity may be determined using standard in vitro bindingassays and/or standard in vivo functionality tests, such as thosedescribed in “Test methods”.

The tropane derivative having dopamine reuptake inhibitor activity foruse according to the invention may in particular be tropane derivativessuch as those disclosed the NeuroSearch patent applications EP 604355,EP 604352, U.S. Pat. No. 5,444,070, EP 604354, WO 95/28401, and WO97/30997, and fused tropane derivatives such as those disclosedNeuroSearch application WO 97/16451.

In one embodiment, the tropane derivative having dopamine reuptakeinhibitor activity shows an IC₅₀ value of less than 1 μM, preferablyless than 100 nM, more preferably less than 50 nM, and even morepreferably less than 10 nM when tested for in vitro inhibition of ³H-DAuptake (test method 1).

In a second embodiment, the tropane derivative having dopamine reuptakeinhibitor activity shows an ED₅₀ value of less than 500 mg/kg,preferably less than 100 mg/kg, more preferably less than 50 mg/kg, morepreferably less than 20 mg/kg, and even more preferably less than 10mg/kg when tested for in vivo inhibition of ³H—WIN 35428 binding p.o.,s.c. or i.p. (test method 5).

In a further embodiment, the tropane derivative having dopamine reuptakeinhibitor activity shows a protection against MPTP of more than 60%,preferably more than 70%, and even more preferably more than 80% at 20mg/kg of the test substance when tested for effect on striatal dopaminein mice treated with MPTP (test method 8). In a still furtherembodiment, the tropane derivative having dopamine reuptake inhibitoractivity shows a protection against MPTP of more than 60%, preferablymore than 70%, and even more preferably more than 80% at 10 mg/kg of thetest substance when tested for effect on striatal dopamine in micetreated with MPTP.

The above examples of tropane derivative having dopamine reuptakeinhibitor activity are not intended to be in any way limiting to thescope of the invention as claimed.

Definition of Substituents

In the context of this invention alkyl designates a straight chain or abranched chain containing of from one to six carbon atoms (C₁-C₆ alkyl),including but not limited to methyl, ethyl, propyl, isopropyl, butyl,isobutyl, t-butyl, pentyl and hexyl. In a preferred embodiment of thisinvention alkyl represents a C₁-C₄ alkyl, preferably a C₁-C3 alkyl, mostpreferred methyl, ethyl, propyl or isopropyl.

In the context of this invention cycloalkyl designates a cyclic alkylcontaining of from three to seven carbon atoms (C₃-C₇ cycloalkyl),including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

In the context of this invention alkenyl designates a group containingof from two to six carbon atoms (C₂-C₆ alkenyl), including at least onedouble bond, for example, but not limited to ethenyl, 1,2- or2,3-propenyl, 1,2-, 2,3-, or 3,4-butenyl.

In the context of this invention alkynyl designates a group containingof from two to six carbon atoms (C₂-C₆ alkynyl), including at least onetriple bond, for example, but not limited to ethynyl, 1,2- or2,3-propynyl, 1,2-, 2,3- or 3,4-butynyl.

In the context of this invention cycloalkyl-alkyl designates acycloalkyl as defined above which is attached to an alkyl as alsodefined above, e.g. cyclopropylmethyl.

In the context of this invention aryl designates an aromatichydrocarbon, such as phenyl or naphthyl.

In the context of this invention alkoxy designates an alkyl-O—, wherealkyl is as defined above.

In the context of this invention acyl designates an alkyl-CO—, wherealkyl is as defined above.

In the context of this invention halogen designates a fluorine, achlorine, a bromine or an iodine atom.

In the context of this invention amino represents NH₂, NH-alkyl, orN-(alkyl)₂, wherein alkyl is as defined above.

In the context of this invention heteroaryl designates a 5- or6-membered heterocyclic monocyclic group, for example, but not limitedto, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl,isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,5-thiadiazol-3-yl,1,2,5-thiadiazol4-yl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl,2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl.

Steric Isomers

The chemical compounds for use in the invention may exist in (+) and (−)forms as well as in racemic forms. The use of racemates of these isomersand the individual isomers themselves are within the scope of thepresent invention.

Racemic forms can be resolved into the optical antipodes by knownmethods and techniques. One way of separating the diastereomeric saltsis by use of an optically active acid, and liberating the opticallyactive amine compound by treatment with a base. Another method forresolving racemates into the optical antipodes is based uponchromatography on an optical active matrix. Racemic compounds of thepresent invention can thus be resolved into their optical antipodes,e.g., by fractional crystallisation of d- or l- (tartrates, mandelates,or camphor-sulphonate) salts for example.

The chemical compounds for use in the invention may also be resolved bythe formation of diastereomeric amides by reaction of the chemicalcompounds of the present invention with an optically active activatedcarboxylic acid such as that derived from (+) or (−) phenylalanine, (+)or (−) phenylglycine, (+) or (−) camphanic acid or by the formation ofdiastereomeric carbamates by reaction of the chemical compound of thepresent invention with an optically active chloroformate or the like.

Additional methods for the resolving the optical isomers are known inthe art. Such methods include those described by Jaques J, Collet A, &Wilen S in “Enantiomers, Racemates, and Resolutions”, John Wiley andSons, New York (1981).

Moreover, some of the chemical compounds for use in the invention maythus exist in two forms, syn- and anti-form (Z- and E-form), dependingon the arrangement of the substituents around a —C═C—or —C═N— doublebond. A chemical compound for use according to the present invention maythus be the syn- or the anti-form (Z- and E-form), or it may be amixture hereof.

Pharmaceutically Acceptable Salts

The tropane derivative having dopamine reuptake inhibitor activity foruse according to the invention may be provided in any form suitable forthe intended administration. Suitable forms include pharmaceutically(i.e. physiologically) acceptable salts, and pre- or prodrug forms ofthe chemical compound for use according to the invention.

Examples of pharmaceutically acceptable addition salts include, withoutlimitation, the non-toxic inorganic and organic acid addition salts suchas the hydrochloride, the hydrobromide, the nitrate, the perchlorate,the phosphate, the sulphate, the formate, the acetate, the aconate, theascorbate, the benzenesulphonate, the benzoate, the cinnamate, thecitrate, the embonate, the enantate, the fumarate, the glutamate, theglycolate, the lactate, the maleate, the malonate, the mandelate, themethanesulphonate, the naphthalene-2-sulphonate derived, the phthalate,the salicylate, the sorbate, the stearate, the succinate, the tartrate,the toluene-p-sulphonate, and the like. Such salts may be formed byprocedures well known and described in the art.

Metal salts of a chemical compound for use according to the inventioninclude alkali metal salts such as the sodium salt of the chemicalcompound containing a carboxy group.

The term “prodrug” denotes a compound, which is a drug precursor andwhich, following administration and absorption, release the drug in vivovia some metabolic process.

Particularly favoured prodrugs are those that increase thebioavailability of the compounds for use according to the invention(e.g. by allowing an orally administrered compound to be more readilyabsorbed into the blood) or which enhance delivery of the parentcompound to a specific biological compartment (e.g. the brain orlymphatic system).

Thus examples of suitable prodrugs of the substances according to theinvention include compounds modified at one or more reactive orderivatizable groups of the parent compound. Of particular interest arecompounds modified at a carboxyl group, a hydroxyl group, or an aminogroup. Examples of suitable derivatives are esters or amides.

Pharmaceutical Compositions

The invention provides the use of pharmaceutical compositions comprisinga therapeutically effective amount of the dopamine reuptake inhibitor.While a tropane derivative having dopamine reuptake inhibitor activityfor use in therapy according to the invention may be administered in theform of the raw chemical compound, it is preferred to introduce theactive ingredient, optionally in the form of a physiologicallyacceptable salt, in a pharmaceutical composition together with one ormore adjuvants, excipients, carriers, buffers, diluents, and/or othercustomary pharmaceutical auxiliaries.

In a preferred embodiment, the invention provides pharmaceuticalcompositions comprising the tropane derivative having dopamine reuptakeinhibitor activity, together with one or more pharmaceuticallyacceptable carriers therefore, and, optionally, other therapeutic and/orprophylactic ingredients, know and used in the art. The carrier(s) mustbe “acceptable” in the sense of being compatible with the otheringredients of the formulation and not harmful to the recipient thereof.

The pharmaceutical composition may be administered by any convenientroute, which suits the desired therapy. Preferred routes ofadministration include oral administration, in particular in tablet, incapsule, in dragé, in powder, or in liquid form, and parenteraladministration, in particular cutaneous, subcutaneous, intramuscular, orintravenous injection. The pharmaceutical composition can bemanufactured by any skilled person by use of standard methods andconventional techniques appropriate to the desired formulation. Whendesired, compositions adapted to give sustained release of the activeingredient may be employed.

Further details on techniques for formulation and administration may befound in the latest edition of Remington's Pharmaceutical Sciences(Maack Publishing Co., Easton, Pa.).

The actual dosage depend on the nature and severity of the disease beingtreated, and is within the discretion of the physician, and may bevaried by titration of the dosage to the particular circumstances ofthis invention to produce the desired therapeutic effect. However, it ispresently contemplated that pharmaceutical compositions containing offrom about 0.1 to about 500 mg of active ingredient per individual dose,preferably of from about 1 to about 100 mg, most preferred of from about1 to about 10 mg, are suitable for therapeutic treatments.

The active ingredient may be administered in one or several doses perday. A satisfactory result can, in certain instances, be obtained at adosage as low as 0.1 μg/kg i.v. and 1 μg/kg p.o. The upper limit of thedosage range is presently considered to be about 10 mg/kg i.v. and 100mg/kg p.o. Preferred ranges are from about 0.1 μg/kg to about 10mg/kg/day i.v., and from about 1 μg/kg to about 100 mg/kg/day p.o.

Combined Treatment

The pharmaceutical composition for use according to the invention mayinclude or may be used or administered in combination with one or moreadditional drugs useful for the treatment, prevention or alleviation ofa disease associated with reduced blood flow to the brain or with aninstance of a temporary break in blood supply to the brain. Suchadditional drugs include compounds capable of blocking excitatory aminoacid receptors (glutamate and aspartate) and neurotrophic compounds

Examples of compounds capable of blocking excitatory amino acidreceptors include those substances described in the patent applicationsWO 94/26747, WO 96/08494, WO 96/08495, WO 98/14447 and WO 99/49864 (allNeuroSearch).

In the context of this invention, compounds with neurotrophic activityare compounds that mimic or enhance the function of one or moreendogenous neurotrophic factors. In one embodiment, a compound withneurotrophic activity is a compound that mimics or enhances the functionof NGF, BDNF, and/or GDNF. In a further embodiment, a compound withneurotrophic activity is a compound that mimics or enhances the functionof bFGF and/or EGF. In a special embodiment, a compound withneurotrophic activity is a compound that mimics or enhances the functionof NGF. The neurotrophic activity has not been ascribed to a specificstep in the interaction between the growth factor and its receptor or inthe growth factor signal transduction pathway. The potential of a givensubstance to act as a compound with neurotrophic activity may bedetermined using standard in vitro binding assays and/or standard invivo functional tests.

Compounds with neurotrophic activity include those substances describedin the patent applications WO 98/07705 (Takeda Chem Ind Ltd), WO00/34262 (Takeda Chem Ind Ltd), WO 00/32197 (Alcon Lab Inc), WO 97/40035(NeuroSearch), WO 00/43397 (NeuroSearch), international application WO01/55110 (NeuroSearch), JP 2000226388-A (Takeda Chem Ind Ltd), WO00/32197 (Alcon Lab), and WO 00/46222 (Schering AG).

Further examples of compounds with neurotrophic activity according tothe invention include1-(1,3-benzodioxol-5-yl)-7,8,9,10-tetrahydro-1,3-benzodioxol[4,5-g]isoquinolin-7-one(Takeda),2-(2,2,4,6,7-Pentamethyl-3-phenyl-2,3-dihydro-1-benzo-furan-5-yl)-isoindoline(Takeda), 4-Aryl-1-phenylalkyl-1,2,3,6-tetrahydropyridine(Sanofi-Synthelabo), SR-57746A or1-(2-napht-2-yl)ethyl-4-(3-trifluoromethylphenyl)-1,2,5,6-tetrahydropyridine(Sanofi-Synthelabo), AIT-082 (NeoTherapeutics), NIL-A (Amgen Inc),K-252a (Cephalon), CEP-1347, GPI-1046 (Guilford), CTQ3, CTQ5 and CTQ8(Centre de Neurochimie du CNRS), V-10,367 and V-13,661 (VertexPharmaceuticals Inc), ABS-205 (American Biogenic Sciences), Dexanabinolor HU-211 (Pharmos), or salts, free bases, racemates or enantiomersthereof.

The above examples of compounds capable of blocking excitatory aminoacid receptors and compounds with neurotrophic activity are not intendedto be in any way limiting to the scope of the invention.

Methods of Preparation

The compounds of general formula (I) and (II) for use in the inventionmay be prepared by conventional methods of chemical synthesis, e.g.those described in the NeuroSearch patent publications EP 604355, EP604352, U.S. Pat. No. 5,444,070, EP 604354, WO 97/30997, WO 95/28401,and WO 97116451.

The starting materials for the processes described in the presentapplication are known or may readily be prepared by conventional methodsfrom commercially available chemicals.

The end products of the reactions described herein may be isolated byconventional techniques, e.g. by extraction, crystallisation,distillation, chromatography, etc.

Any possible combination of two or more of the embodiments described inthis patent application is comprised within the scope of the presentinvention.

The invention is further illustrated with reference to the followingtest methods and examples which are not intended to be in any waylimiting to the scope of the invention as claimed.

TEST METHODS

Method 1

In Vitro Inhibition of ³H-dopamine (³H-DA) Uptake in StriatalSynaptosomes

In this test, the ability of dopamine reuptake inhibitor (below: thetest compound) to inhibit the uptake of ³H-dopamine in striatalsynaptosomes is assessed.

Tissue preparations: Preparations are performed at 0-40° C. unlessotherwise indicated. Corpi striati from male Wistar rats (150-200 g) arehomogenised for 5-10 sec in 100 volumes of ice-cold 0.32M sucrosecontaining 1 mM pargyline using an Ultra-Turrax homogenizer. Monoamineoxidase activity will be inhibited in the presence of pargyline. Thehomogenate is centrifuged at 1000×g for 10 min. The resultingsupernatant is then centrifuged at 27,000×g for 50 min and thesupernatant is discarded. The pellet (P₂) is resuspended in oxygenated(equilibrated with an atmosphere of 96% O₂: 4% CO₂ for at least 30 min)Krebs-Ringer incubation buffer (8000 ml per g of original tissue) at pH7.2 containing 122 mM NaCl, 0.16 mM EDTA, 4.8 mM KCl, 12.7 mM Na₂HPO₄,3.0 mM NaH₂PO₄, 1.2 mM MgSO₄, 1 mM CaCl₂, 10 mM glucose and 1 mMascorbic acid.

Assay: Aliquots of 4.0 ml tissue suspension are added to 100 μl of testsolution and 100 μl of ³H-DA (1 nM, final concentration), mixed andincubated for 25 min at 37° C. Non-specific uptake is determined usingbenztropine (10 μM, final concentration). After incubation the samplesare poured directly onto Whatman GF/C glass fibre filters under suction.The filters are then washed three times with 5 ml of ice-cold 0.9% (w/v)NaCl solution. The amount of radioactivity on the filters is determinedby conventional liquid scintillation counting. Specific uptake iscalculated as the difference between total uptake and non-specificuptake.

25-75% inhibition of specific binding must be obtained, beforecalculation of an IC₅₀. The test value is given as IC₅₀ (theconcentration (μM) of the test compound which inhibits the specificbinding of ³H-DA by 50%).

Method 2

Inhibition of DA Uptake in Rat Brain Synaptosomes

In this method the ability of test compounds to inhibit the activity ofdopamine transporter proteins is measured in vitro by analyzing thesynaptosomal uptake of [³H]dopamine ([³H]DA).

Tissue Preparation: Preparations are performed at 0-4° C. unlessotherwise indicated. The striata from male Wistar rats (150-200 g) arehomogenized for 5-10 sec in 100 volumes of ice-cold 0.32 M sucrosecontaining 1 mM pargyline using a motor driven teflon pestle in a glasshomogenizing vessel. Monoamine oxidase activity is inhibited in thepresence of pargyline. The homogenates are centrifuged at 1000×g for 10min. The resulting supematants are then centrifuged at 27,000×g for 50min. The supernatants are discarded and the pellets (P₂) are resuspendedin oxygenated (equilibrated with an atmosphere of 96% O₂: 4% CO₂ for atleast 30 min) Krebs-Ringer incubation buffer (pH 7.2) (8000 ml per g oforiginal tissue for the [³H]DA assay) containing 122 mM NaCl, 0.16 mMEDTA, 4.8 mM KCl, 12.7 mM Na₂HPO₄, 3.0 mM NaH₂PO₄, 1.2 mM MgSO₄, 0.97 mMCaCl₂, 10 mM glucose and 1 mM ascorbic acid.

Uptake assays: Aliquots of 4.0 ml tissue suspension are added to 0.1 mlof test solution and 0.1 ml of [³H]DA (1 nM, final concentration), mixedand incubated for 25 min at 37° C. Non-specific uptake is determined inthe presence of benztropine (1 μM, final concentration). Afterincubation the samples are poured directly onto Whatman GF/C glass fibrefilters under suction. The filters are then washed three times with 5 mlof ice-cold 0.9% (w/v) NaCl solution. The amount of radioactivity on thefilters is determined by conventional liquid scintillation countingusing a Tri-carb™ liquid scintillation analyzer (model 1600CA; Packard,USA) Specific uptake is calculated as the difference between totaluptake and non-specific uptake.

Data analysis: The test value is given as an IC₅₀ (the concentration(μM) of the test substance which inhibits the specific uptake of[³H]ligand by 50%).

Three concentrations are been used to determine the inhibition curvesfrom which the IC₅₀ values are determined. If a full curve is notavailable a 25-75% inhibition of specific binding must be obtained,before calculation of an IC₅₀.IC₅₀=(applied test substance concentration,${IC}_{50} = {\left( {{{applied}\quad{test}\quad{substance}\quad{concentration}},\quad{µ\quad M}} \right) \times \frac{1}{\left( {\frac{C_{o}}{C_{x}} - 1} \right)}}$where C_(o) is specific uptake in control assays and C_(x) is thespecific uptake in the test assay. (The calculations assume normalmass-action kinetics).Method 3Inhibition of in Vitro [³H]GBR 12935 Binding to the Dopamine Transporterin Rat Striatal Synaptosomes

In this method the ability of test compounds to inhibit the binding ofGBR 12935 to the dopamine transporter in vitro is assessed.

Tissue preparation: Preparations are performed at 0-4° C. unlessotherwise indicated. Striata from male Wistar rats (150-200 g) arehomogenized for 5-10 sec in 10 ml Tris-citrate buffer (50 mM, pH 7.1)using an Ultra-Turrax homogenizer. The suspension is centrifuged at27,000×g for 15 min. The supematant is discarded and the pellet isresuspended in Tris-citrate buffer containing 120 mM NaCl and 4 mM MgCl₂(7000 ml per g of original tissue) and used for binding assays.

Binding assays: Aliquots of 1.0 ml tissue suspension are added to 0.050ml of test solution and 0.050 ml of [³H]GBR 12935 (0.5 nM, finalconcentration), mixed and incubated for 60 min at 2° C. Non-specificbinding is determined using GBR 12909 (1 μM, final concentration).

After incubation 5 ml of ice-cold buffer is added to the samples andpoured directly onto Whatman GF/C glass fiber filters (for the [³H]GBR12935 assay the filters are presoaked in 0.1% PEI for at least 20 min)under suction and immediately washed with 5 ml ice-cold buffer. Theamount of radioactivity on the filters is determined by conventionalliquid scintillation counting using a Tri-carb liquid scintillationanalyzer (model 1600CA; Packard, USA). Specific binding is calculated asthe difference between total binding and non-specific binding.

Data analysis: The test value is given as an IC₅₀ (the concentration(μM) of the test substance which inhibits the specific binding of[³H]ligand by 50%).

Five to nine concentrations are been used to determine the inhibitioncurves from which the IC₅₀ values are determined. If a full curve is notavailable a 25-75% inhibition of specific binding must be obtained,before calculation of an IC₅₀.IC₅₀=(applied test substance concentration,${IC}_{50} = {\left( {{{applied}\quad{test}\quad{substance}\quad{concentration}},\quad{µ\quad M}} \right) \times \frac{1}{\left( {\frac{C_{o}}{C_{x}} - 1} \right)}}$where C_(o) is specific binding in control assays and C_(x) is thespecific binding in the test assay. (The calculations assume normalmass-action kinetics).Method 4Inhibition of in vitro [³H]WIN 35428 Binding to the Dopamine Transporterin Rat Striatal Synaptosomes

In this method the ability of test compounds to inhibit the binding ofWIN 35428 to the dopamine transporter in vitro is assessed.

Tissue preparation: Striata from male Wistar rats (150-200 g) arehomogenized for 5-10 sec in 10 ml NaH₂PO₄ (50 mM, pH 7.4) using anUltra-Turrax homogenizer. The suspension is centrifuged at 27,000×g for15 min. The supernatant is discarded and the pellet is resuspended inphosphate buffer (1000 ml per g of original tissue) and used for bindingassays.

Binding assays: Aliquots of 0.5 ml tissue suspension are added to 0.025ml of test solution and 0.025 ml of [³H]WIN 35428 (1 nM, finalconcentration), mixed and incubated for 60 min at 2° C. Non-specificbinding is determined using cocaine (30 μM, final concentration).

After incubation 5 ml of ice-cold buffer is added to the samples andpoured directly onto Whatman GF/C glass fiber filters (for the [³H]GBR12935 assay the filters are presoaked in 0.1% PEI for at least 20 min)under suction and immediately washed with 5 ml ice-cold buffer. Theamount of radioactivity on the filters is determined by conventionalliquid scintillation counting using a Tri-carb liquid scintillationanalyzer (model 1600CA; Packard, USA). Specific binding is calculated asthe difference between total binding arid non-specific binding.

Data analysis: The test value is given as an IC₅₀ (the concentration(μM) of the test substance which inhibits the specific binding of[³H]ligand by 50%).

Five to nine concentrations are been used to determine the inhibitioncurves from which the IC₅₀ values are determined. If a full curve is notavailable a 25-75% inhibition of specific binding must be obtained,before calculation of an IC₅₀.IC₅₀=(applied test substance concentration,${IC}_{50} = {\left( {{{applied}\quad{test}\quad{substance}\quad{concentration}},\quad{µ\quad M}} \right) \times \frac{1}{\left( {\frac{C_{o}}{C_{x}} - 1} \right)}}$where C_(o) is specific binding in control assays and C_(x) is thespecific binding in the test assay. (The calculations assume normalmass-action kinetics).Method 5Inhibition of in Vivo [³H]WIN 35428 Binding

The test substance is administered to groups of three female NMRI mice(25 g) at specified time points, either i.v., i.p., s.c. or p.o.Forty-five min before decapitation the mice are injected i.v. via thetail vein with 2.0 μCi of [³H]WIN 35428 in 0.25 ml saline. At the timeof decapitation the striata are rapidly dissected on ice. Each striatumis weighed and dissolved for 36 h with 1 ml of 2% sodium-laurylsulfate.Two ml of scintillation cocktail is added to the solubilized tissue, andthe amount of radioactivity per mg of tissue is determined byconventional liquid scintillation counting using a Tri-carb™ liquidscintillation analyzer (model 1600CA; Packard, USA). Groups of vehicletreated mice serves as controls. To determine non-specific binding,groups of mice are injected with WIN 35428 (2.5 mg/kg i.p.; 0.75 ml) atthe time of [³H]WIN 35428 injection. Specific binding is calculated asthe difference between binding in vehicle and WIN 35428 treated mice.

Data analysis: The test value is given as an ED₅₀ (the dose (mg/kg) ofthe test substance which inhibits the specific binding of [³H]WIN 35428by 50%).

Three doses of test substance are used to determine the dose responsecurve from which the ED₅₀ value is determined. If a full curve is notavailable a 25-75% inhibition of specific binding must be obtainedbefore calculation of an ED₅₀ value.ED₅₀=(administered test substance dose,${ED}_{50} = {\left( {{{administered}\quad{test}\quad{substance}\quad{dose}},{{mg}\text{/}{kg}}} \right) \times \frac{1}{\left( {\frac{C_{o}}{C_{x}} - 1} \right)}}$where C_(o) is specific binding in controls and C_(x) is the specificbinding in mice treated with test substance.Method 6Protection of the Hippocampus after Transient Global Ischaemia inGerbils

In this experiment, the neuroprotective effect of a test compound isassessed in an animal model of transient global ischaemia.

Method: In halothane anaesthetised gerbils, right and left carotidarteries are located and occluded for 4 minutes. Animals are kept atnormal body temperature before and after the operation using heatinglamps. During surgery, the gerbils are placed on heating pads, the bodytemperature is controlled and maintained at 37±0.5° C. The test compoundis dosed at specified time points after the ischaemic insult, eitheri.v., i.p., s.c. or p.o.

Four days later, the animals are sacrificed, brains removed and cooledto −70° C. Thereafter, the brains are sectioned in 20 μm thick sectionsof which 5-7 with hippocampal tissue are selected and stained withhematoxylin-eosin.

The degree of hippocampal damage is categorised into one of four groups:

-   -   Group 1: no damage in the CA₁-layer;    -   Group 2: the CA₁-layer partly damaged;    -   Group 3: the CA₁-layer completely damaged; and    -   Group 4: damage in more than just the CA₁-layer.

The total ischaemia score is obtained as the sum of scores in the right-and left hemisphere. Kendall's tau test was used for statisticevaluation.

Method 7

Protection of the Substantia Nigra after Transient Global Ischaemia inGerbils

In this experiment, the neuroprotective effect of a test compound isassessed in an animal model of transient global ischaemia.

Method: In halothane anaesthetised gerbils, right and left carotidarteries are located and occluded for 10 minutes. Animals are kept atnormal body temperature before and after the operation using heatinglamps. During surgery, the gerbils are placed on heating pads, the bodytemperature is controlled and maintained at 37±0.5° C. The test compoundis dosed at specified time points after the ischaemic insult, eitheri.v., i.p., s.c. or p.o.

Fourteen days later, the animals are sacrificed, brains removed andcooled to −70° C. Thereafter, the brains are sectioned in 20 μm thicksections through the substantia nigra region. Sections are stained fortyroxine hydroxylase (TH+) expression using immunohistochemistry. Thenumber of TH+ cells in the sections is counted and the total number ofTH+ cells in the substantia nigra is calculated by means of stereology.

Method 8

Transient Global Ischaemia in Gerbils

In this experiment, the neuroprotective effect of a test compound isassessed in an animal model of transient global ischaemia.

Method: In halothane anaesthetised gerbils, right and left carotidarteries are located and occluded for 4 minutes. Animals are kept atnormal body temperature before and after the operation using heatinglamps. During surgery, the gerbils are placed on heating pads, the bodytemperature is controlled and maintained at 37±0.5° C. The test compoundis dosed at specified time points after the ischaemic insult, eitheri.v., i.p., s.c. or p.o.

Four days later, the animals are sacrificed, brains removed and cooledto −70° C. Thereafter, the brains are sectioned in 20 μm thick sectionsof which 5-7 with hippocampal tissue are selected and stained withhematoxylin-eosin.

The degree of hippocampal damage is categorised into one of four groups:

-   -   Group 1: no damage in the CA₁-layer;    -   Group 2: the CA₁-layer partly damaged;    -   Group 3: the CA₁-layer completely damaged; and    -   Group 4: damage in more than just the CA₁-layer.

The total ischaemia score is obtained as the sum of scores in the right-and left hemisphere. Kendall's tau test was used for statisticevaluation.

Method 9

Mouse Middle Cerebral Artery Occlusion (MCAO)

In this experiment, the neuroprotective effect of a compound is assessedin an animal model of focal ischaemia.

Female NMRI-mice (27-38 g) are anaesthetized with halothane (2%halothane in 30% O₂-70% NO₂). During surgery the body temperature ismaintained at 37±0.5° C. by placing the mice on heating pads connectedto a CMA/150 temperature controller. MCAO is performed as earlierdescribed (Møller et al., Neurol Res, 17, 353-360, 1995). After MCAO,the mice are placed under heating lamps. The test compound isadministrated at specified time points after the ischaemic insult,either i.v., i.p., s.c. or p.o. The control group is given vehicle. Onthe fourth day, the mice are sacrificed and the brains removed. Thebrains are frozen on dry ice and cut into 20 μm sections. Every 40^(th)sections are sampled and the total infarct volume is used as theendpoint for ischemic damage. The infarct volume is estimated using theCavalieri's volume estimator (Gundersen et al., AMPIS, 96, 379-394,1998).

Method 10

Effect of a Compound on Striatal Dopamine in Mice Treated with MPTP

In this test, the ability of compound to increase striatal dopamine inmice treated with MPTP is assessed.

Female C57BL/6J mice weighing 20-25 grams (Møollegaard Breeding andResearch Centre) are adapted to the laboratory for 5-7 days before theexperiments with food and water freely available, room temperature22-24° C. Light is on/off at 7 am and 6 pm, respectively. At least 5-8mice are used per group. MPTP, HCL (RBI) is dissolved in saline justbefore the experiments and is tested in various doses 12.5, 25, 3×12.5and 3×25 mg/kg sc. The test compound is tested following a pretreatmenttime between 30 min and 3 hrs before the subcutaneous sc injection ofMPTP 25 mg/kg. The mice are sacrificed 48 hrs after the last dose ofMPTP for the biochemical analysis of dopamine and its metabolites HVAand DOPAC. For biochemical analysis, the striatum of the mice is rapidlydissected out, frozen and stored at −80° C. On the day of analysis, onestriatum per mouse (weighing 5-7 mg) is homogenised in 1 ml of 0.1 NPerchloric acid containing 5% EDTA . After centrifugation 14,0000×G for30 min. 200 μl of the supernatant is filtered through a glass 0.22 μmfilter. 20 μl is then injected into our ESA Coulochem II HPLC equipmentwith a the following column (Caracholamine HR-80 4.6 mm×80 mm 3 umNucleosil C 18). The eluent is 10.25 g NaH₂ PO₄, 185 mg EDTA, 100 mgOctansulphonic acid. 9% methanol, pH 3.7, add 500 ml MiliQ water,filtered through 0.22 um. The Colochem ESA analytical cell is 5014A andthe ESA detector has the following settings: E₂ −175 mV, run time 16min. for the elution of dopamine, DOPAC and HVA (DOPAC=4.3 min;dopamine=6.4 min and HVA=12.7 min.). The autoinjector SHIMADZY sil-10Ahas the following settings; injection vol. 20 μl, 16 min analysis, temp4° C. Flow rate from the pump is 0.80 m/min. The analyses are calibratedwith standards of 3 pM of dopamine, HVA and DOPAC for each 12 analysisrun and are compared with our standard curves.

Method 11

Effect of a Compound on Extracellular Dopamine Measured by Microdialysis

In this test, the ability of a compound to increase dopamine in variousbrain regions is assessed.

Male SPF Mol Wistar rats weighing 300-350 g are obtained from MøllegaardBreeding and Research Centre and housed in standard Macrolon cages sized24×36×18 cm for at least 5 days under standard conditions at atemperature of 23±2° C. and a humidity of 60%±10%, and a 12 h light anddark cycle. The rats are housed in groups of two with food and waterfreely available ad libitum. For microdialysis, the rat is placed in astereotaxic instrument under halothane anesthesia using 1{fraction(1/2)}% halothane, 20% oxygen and 80% nitrous oxide. The rectaltemperature is monitored and maintained at 37.0±1° C. during theexperimental period using a heating pad (CMA 150 Camegie Medicin). Asmall hole is drilled to allow a vertical probe (CMA/123), to bestereotaxically implanted into the right striatum, using the followingcoordinates relative to bregma : AP +1 mm; L 3 mm; DV −6 mm. The probesfor the nucleus accumbens (CMA 122) is implanted vertical at thefollowing coordinates: AP +2.4, L1.4 and DV −8 mm. Similar experimentsare performed with probes implanted into the nucleus accumbens in nonanaesthetised freely moving animals. These experiments are performed 48h after surgery during the daylight period in animals housedindividually in plastic cages with food and water available ad libitum.In all cases, the injection sites are confirmed histologically accordingto the atlas of Paxinos and Watson.

After an initial 2 h period, samples of dialysate are collected fromhalothane anaesthetised rats. The dosing of a test compound to theserats are usually initiated after the collection of 3 base line analyses.Dopamine and its metabolites are rapidly frozen to −18° C. and thenanalyzed as soon as possible thereafter. The dialysis probe is perfusedat a rate of 2 μl/min (by a CMA/100 microperfusion pump) with Ringer'ssolution (147 mM NaCl, 4 mM KCl, 2.3 mM CaCl) i.e. Ringer's solution(NaCl 4.3 g, KCl 150 mg, CaCl₂ 110.3 mg ad 500 ml) adjusted to pH 6.5with 2 mM sodium phosphate buffer. The Ringer solution is filteredbefore use through Millipore glass filters (0.22 μm). The dialysatefractions (40 μl) are collected at 20 min intervals and then injectedinto the HPLC system. The concentration of dopamine (DA), dihydroxyphenyl acetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA) are determined by high-performance liquidchromatography with electrochemical detection (HPLC-ED). The column is areverse-phase liquid chromatography Catecholamine 3 μm ESA column at 23°C., the mobile phase consisting of 0.055 M sodium acetate with 0.1 nMoctanesulfonic acid, 0.01 mM Na EDTA, and 10% methanol pH 3.7 adjustedwith glacial acetic acid). The mobil phase is delivered by a HPLC pump(ESA) at 0.55 ml/min. Electrochemical detection is accomplished using anamperometric detector (Antec) with a glassy carbon electrode (0.8 V anAg/AgCl reference) or a coloumetric detector (Choulochem II model ESA;with a high sensitivity analytical cell (5011). (0.4V an Ag/AgClreference). Chromatograms are recorded by an integrator. The data arecalculated as percent change of the basal concentration, the 100% valuebeing defined as the average of the last 3 pretreatment values for eachrat. The mean percentage values are then calculated for each 20 minsample for the rats in each group of treatment.

Method 12

Effect of a Compound on Turning Behaviour after 6-OHDA Lesion

In this test, the ability of a compound to influence the turningbehaviour after a striatal or medial forebrain bundle and ventraltegmental area 6-OHDA lesion is assessed.

6-OHDA (20 μg free base dissolved in 0.9% NaCl supplemented with 0.02%ascorbic acid) is injected unilaterally in the striatum or in the medialforebrain bundle and the ventral tegmental area of halothaneanaesthetised female Sprague Dawley rats weighing approximately 200-250g with a glass capillary. Test compound or vehicle is administered i.p.,p.o., s.c. or i.v. either daily or at specified time points startingafter the 6-OHDA injection. The rotational behaviour of the 6-OHDAlesioned animals is monitored in automated rotometer bowls afteradministration of test compound alone or after administration ofamphetamine (2.5 mg/kg i.p.), apomorphine (0.25 mg/kg s.c.), or L-dopa(2-10 mg/kg i.p.).

EXAMPLES Example 1

Protection of the Substantia Nigra after Transient Global Ischaemia inGerbils

Global forebrain ischemia was induced in Mongolian gerbils as describedin test method 7 by occluding the common carotid arteries bilaterallyfor 10 min. The experiment was carried out for the following threegroups of animals: 1) a control group (6 animals), 2) a group of animalssubjected to carotid artery occlusion ischemia (6 animals) and 3) agroup subjected to carotid artery occlusion ischemia and treatment withthe test compound (8 animals). The animals of the control group weresubjected to the same surgical procedure as group 2) except for theocclusion. The following test compound was used:(1R,2R,3S)-3-(3,4-dichlorophenyl)-tropane-2-O-methyl-aldoxime. The testcompound was dosed 2 minutes after end of carotid artery occlusion at aconcentration of 2 mg/kg i.p.

After 14 days, the animals were sacrificed and the brains sectioned.Sections comprising the substantia nigra were TH immunostained. Thetotal number of TH positive cells after ischemia or in control animalswere determined by means of stereological cell counting.

The results are shown in Table 1. In animals subjected to ischemia, thetotal number of TH positive cells in the substantia nigra (7510±1185)appeared to be lower than that in control animals (9531±653) indicatingischemia induced cell death in the substantia nigra. Surprisingly, thenumber of surviving TH positive cells in the substantia nigra afterischemia was apparently increased by treatment with the test compoundindicating that this compound has a protective effect in ischemia. GroupMean number of cells SEM (number of cells) Control 9531 653 Ischemia7510 1185 Ischemia + 10615 1403 test compound

1. A method for the treatment, prevention or alleviation of diseasesassociated with reduced blood flow to the brain or with an instance of atemporary break in blood supply to the brain in a subject, comprisingadministering to said subject a therapeutically effective amount of atropane derivative having dopamine reuptake inhibitor activity or apharmaceutically acceptable salt thereof.
 2. The method according toclaim 1, wherein the tropane derivative having dopamine reuptakeinhibitor activity is a compound of the general formula (I)

or a pharmaceutically acceptable addition salt thereof or the N-oxidethereof, wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl or 2-hydroxyethyl; R³ is CH₂—X—R′, wherein X is O, S, orNR″; wherein R″ is hydrogen or alkyl; and R′ is alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, or —CO-alkyl; heteroaryl which may besubstituted one or more times with alkyl, cycloalkyl, orcycloalkylalkyl; phenyl which may be substituted one or more times withsubstituents selected from the group consisting of halogen, CF₃, CN,alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl;phenylphenyl; pyridyl which may be substituted one or more times withsubstituents selected from the group consisting of halogen, CF₃, CN,alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; thienylwhich may be substituted one or more times with substituents selectedfrom the group consisting of halogen, CF₃, CN, alkoxy, alkyl, alkenyl,alkynyl, amino, nitro, and heteroaryl; or benzyl which may besubstituted one or more times with substituents selected from the groupconsisting of halogen, CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl, amino,nitro, and heteroaryl; or (CH₂)_(n)CO₂R¹¹, COR¹¹, or CH₂R¹²; wherein R¹¹is alkyl, cycloalkyl, or cycloalkylalkyl; phenyl which may besubstituted one or more times with substituents selected from the groupconsisting of halogen, CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl, amino,nitro, and heteroaryl; phenylphenyl; pyridyl which may be substitutedone or more times with substituents selected from the group consistingof halogen, CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, andheteroaryl; thienyl which may be substituted one or more times withsubstituents selected from the group consisting of halogen, CF₃, CN,alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; orbenzyl; n is 0 or 1; and R₁₂ is O-phenyl which may be substituted one ormore times with substituents selected from the group consisting ofhalogen, CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, andheteroaryl; or O—CO-phenyl which may be substituted one or more timeswith substituents selected from the group consisting of halogen, CF₃,CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; orCH═NOR′; wherein R′ is hydrogen; alkyl, cycloalkyl, cycloalkylalkyl,alkenyl, alkynyl or aryl; all of which may be substituted with —COOH;—COO-alkyl; —COO-cycloalkyl; or phenyl which may be substituted one ormore times with substituents selected from the group consisting ofhalogen, CF₃, CN, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkenyl,alkynyl, amino, and nitro; R⁴ is 3,4-methylenedioxyphenyl or phenyl,benzyl, naphthyl, or heteroaryl all of which may be substituted one ormore times with substituents selected from the group consisting ofhalogen, CF₃, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl,alkynyl, amino, nitro, and heteroaryl.
 3. The method according to claim2, wherein R³ is 1,2,4-oxadiazol-3-yl which may by substituted in the 5position with alkyl, cycloalkyl, or cycloalkylalkyl; phenyl which may besubstituted one or more times with substituents selected from the groupconsisting of halogen, CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl, amino,nitro, and heteroaryl; phenylphenyl; or benzyl which may be substitutedone or more times with substituents selected from the group consistingof halogen, CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, andheteroaryl; or 1,2,4-oxadiazol-5-yl which may by substituted in the 3position with alkyl, cycloalkyl, or cycloalkylalkyl; phenyl which may besubstituted one or more times with substituents selected from the groupconsisting of halogen, CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl, amino,nitro, and heteroaryl; phenylphenyl; benzyl which may be substituted oneor more times with substituents selected from the group consisting ofhalogen, CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, andheteroaryl; pyridyl which may be substituted one or more times withsubstituents selected from the group consisting of halogen , CF₃, CN,alkoxy, alkyl, alkenyl, alkynyl, amino, nitro and heteroaryl; or thienylwhich may be substituted one or more times with substituents selectedfrom the group consisting of halogen, CF₃, CN, alkoxy, alkyl, alkenyl,alkynyl, amino, nitro and heteroaryl.
 4. The method according to claim2, wherein R³ is —CH₂—X—R′, wherein X is O or S, and R′ is methyl,ethyl, propyl, or cyclopropylmethyl; CH═NOR′; wherein R′ is hydrogen oralkyl, or 1,2,4-oxadiazol-5-yl which may by substituted in the 3position with alkyl.
 5. The method according to claim 1, wherein thetropane derivative having dopamine reuptake inhibitor activity is acompound of the general formula (II)

or any of its enantiomers or any mixture thereof, a pharmaceuticallyacceptable addition salt thereof or the N-oxide thereof wherein X and Ytogether forms ═O, ═S, ═NOR², ═CR³R⁴, ═N—CN, ═N—NR⁷R⁸, —(CH₂)_(m)—, or—W′—(CH₂)^(p)—W″—, or one of X and Y is hydrogen and the other is —OR⁵,—SR⁵, or —NR⁵R⁶ Z is hydrogen, —COOR⁹; R³ and R⁴ are independentlyhydrogen, halogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl,alkoxy, aryl, arylalkyl, or —(CH₂)_(q)—COOR²; R², R⁵ and R⁶ areindependently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl,alkynyl, aryl, or arylalkyl, —CO-alkyl, or —SO₂-alkyl; R⁷ and R⁸ areindependently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl,alkynyl, aryl, or arylalkyl; R⁹ is alkyl, alkenyl or alkynyl; R¹ isalkyl, alkenyl, alkynyl, aryl, or arylalkyl; where said aryl groups maybe substituted one or more times with substituents selected from thegroup consisting of halogen, CF₃, CN, alkoxy, cycloalkoxy, alkyl,cycloalkyl, alkenyl, alkynyl, amino, alkylamino, dialkylamino and nitro;W′ and W″ are each independently O or S; n is 1, 2, 3, or 4; m is 2, 3,4, or 5; p is 1, 2, 3, 4, or 5; and q is 0, 1, 2, 3, or
 4. 6. The methodaccording to claim 1, wherein the tropane derivative having dopaminereuptake inhibitor activity is selected from(1R,2R,3S)-2-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-3-(4-fluorophenyl)tropane;(1R,2R,3S)-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)-3-(4-fluorophenyl)tropane;(1R,2R,3S)-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)-3-(4-methylphenyl)-tropane;(1R,2R,3S)-2-(3-Benzyl-1,2,4-oxadiazol-5-yl)-3-(4-fluorophenyl)tropane;(1R,2R,3S)-2-(3-(4-Phenyl-phenyl)-1,2,4-oxadiazol-5-yl)-3-(4-fluorophenyl)tropane;(1R,2R,3S)-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)-3-(2-naphthyl)tropane;(1R,2R,3S)-3-(3,4-Dichlorophenyl)tropane-2-aldoxime;(1R,2R,3S)-3-(3,4-Dichlorophenyl)-tropane-2-O-methyl-aldoxime;(1R,2R,3S)-3-(3,4-Dichlorophenyl)tropane-2-O-benzyl-aldoxime;(1R,2R,3S)-3-(3,4-Dichlorophenyl)tropane-2-O-ethoxycarbonylmethyl-aldoxime;(1R,2R,3S)-3-(3,4-Dichlorophenyl)tropane-2-O-methoxycarbonylmethyl-aldoxime;(1R,2R,3S)-3-(3,4-Dichlorophenyl)tropane-2-O-(1-ethoxycarbonyl-1,1-dimethyl-methyl)-aldoxime;(1R,2R,3S)-3-(3,4-Dichlorophenyl)tropane-2-O-carboxymethyl-2-aldoxime;(1R,2R,3S)—N-Normethyl-3-(3,4-dichlorophenyl)tropane-2-O-methyl-aldoxime;(1R,2R,3S)—N-Normethyl-3-(3,4-dichlorophenyl)tropane-2-O-benzyl-aldoxime;(1R,2R,3S)-3-(4-Methylphenyl)tropane-2-O-methyl-aldoxime;(1R,2R,3S)-3-(3,4-Dichlorophenyl)tropane-2-O-(1,1-dimethylethyl)-aldoxime;(1R,2R,3S)-3-(4-Chlorophenyl)tropane-2-O-aldoxime;(1R,2R,3S)-3-(4-Chlorophenyl)tropane-2-O-methylaldoxime hydrochloride;(1R,2R,3S)-3-(4-Chlorophenyl)tropane-2-O-methoxycarbony1methyl-aldoxime;(1R,2R,3S)-3-(3,4-Dichlorophenyl)tropane-2-O-(2-propynyl)-aldoxime;(1R,2R,3S)-3-(3,4-Dichlorophenyl)tropane-2-O-(2-methylpropyl)-aldoxime;(1R,2R,3S)-3-(3,4-Dichlorophenyl)tropane-2-O-cyclopropylmethyl-aldoxime;(1R,2R,3S)-3-(3,4-Dichlorophenyl)tropane-2-O-ethyl-aldoxime;(1R,2R,3S)-2-Methoxymethyl-3-(3,4-dichlorophenyl)-tropane;(1R,2R,3S)-2-Isopropoxymethyl-3-(3,4-dichlorophenyl)-tropane;(1R,2R,3S)-2-Ethoxymethyl-3-(3,4-dichlorophenyl)-tropane;(1R,2R,3S)-2-Cyclopropylmethyloxymethyl-3-(3,4-dichlorophenyl)-tropane;(1R,2R,3S)-2-Methoxymethyl-3-(4-chlorophenyl)-tropane;(1R,2R,3S)—N-Normethyl-2-methoxymethyl-3-(4-chlorophenyl)-tropane;(1R,2R,3S)-2-Ethoxymethyl-3-(4-chlorophenyl)-tropane;(1R,2R,3S)—N-Normethyl-2-methoxymethyl-3-(3,4-dichlorophenyl)-tropane;(1R,2R,3S)—N-Normethyl-2-ethoxymethyl-3-(3,4-dichlorophenyl)-tropane;(1R,2R,3S)—N-Normethyl-2-ethoxymethyl-3-(4-chlorophenyl)-tropane;(1R,2R,3S)—N-Normethyl-2-cyclopropylmethyloxymethyl-3-(4-chlorophenyl)-tropane;(1R,2R,3S)-2-Cyclopropylmethyloxymethyl-3-(4-chlorophenyl)-tropane;(1R,2R,3S)-2-Ethylthiomethyl-3-(3,4-dichlorophenyl)-tropane;(1R,2R,3S)-2-Hydroxymethyl-3-(4-fluorophenyl)tropane;(1R,2R,3S)-2-Hydroxymethyl-3-(3,4-dichlorophenyl)tropane;(1R,2R,3S)—N-Normethyl-N-(tert-butoxycarbonyl)-2-hydroxymethyl-3-(3,4-dichlorophenyl)tropane;(1R,2R,3S)-2-Hydroxymethyl-3-(4-chlorophenyl)tropane;(1R,2R,3S)-2-(3-(2-Furanyl)-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane;(1R,2R,3S)-2-(3-(3-Pyridyl)-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane;(1R,2R,3S)—N-Normethyl-N-allyl-2-(3-(4-pyridyl)-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane;(1R,2R,3S)—N-Normethyl-N-ethyl-2-(3-(4-pyridyl)-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane;(1R,2R,3S)—N-Normethyl-N-(2-hydroxyethyl)-2-(3-(4-pyridyl)-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane;(1R,2R,3S)—N-Normethyl-2-(3-(4-pyridyl)-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane;(1R,2R,3S)—N-Normethyl-N-allyl-2-(3-(3-pyridyl)-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane;(1R,2R,3S)—N-Normethyl-N-allyl-2-(3-(2-pyridyl)-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane;(1R,2R,3S)-2-(3-(2-Thienyl)-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)-tropane;(1R,2R,3S)-2-(3-(2-Thienyl)-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane;(1R,2R,3S)-2-(3-(4-Pyridyl)-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane;(1R,2R,3S)-2-(3-(2-Pyridyl)-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane;(1R,2R,3S)-2-(3-(4-Pyridyl)-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)-tropane;(1R,2R,3S)-2-(3-(3-Pyridyl)-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)-tropane;(1R,2R,3S)-2-(3-(2-Pyridyl)-1,2,4-oxadiazol-5-yl)-3-(4,-chlorophenyl)-tropane;(1R,2R,3S)-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)-3-(4-fluorophenyl)-tropane;(1R,2R,3S)-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)-3-(4-methylphenyl)-tropane;(1R,2R,3S)-2-(3-Benzyl-1,2,4-oxadiazol-5-yl)-3-(4-fluorophenyl)-tropane;(1R,2R,3S)-2-(3-(4-Phenylphenyl)-1,2,4-oxadiazol-5-yl)-3-(4-fluorophenyl)-tropane;(1R,2R,3S)-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)-3-(2-naphthyl)-tropane;(1R,2R,3S)-2-(4-Chlorophenoxy-methyl)-3-(4-fluorophenyl)-tropane;(1R,2R,3S)-2-(4-Chlorophenoxy-methyl)-3-(4-fluorophenyl)-tropane;(1R,2R,3S)-2-(4-Chlorophenoxy-methyl)-3-(3,4-dichlorophenyl)-tropane;(1R,2R,3S)-2-(4-Chlorophenoxy-methyl)-3-(4-methylphenyl)-tropane;(1R,2R,3S)-2-(4-Benzoyloxy-methyl)-3-(4-fluorophenyl)-tropane;(1R,2R,3S)-2-Carbomethoxy-3-(2-naphthyl)-tropane;(1R,2R,3S)-2-Carbomethoxy-3-(3,4-dichlorophenyl)-tropane;(1R,2R,3S)-2-Carbomethoxy-3-benzyl-tropane;(1R,2R,3S)-2-Carbomethoxy-3-(4-chlorophenyl)-tropane;(1R,2R,3S)-2-Carbomethoxy-3-(4-methylphenyl)-tropane;(1R,2R,3S)-2-Carbomethoxy-3-(1-naphthyl)-tropane;(1R,2R,3S)-2-Carbomethoxy-3-(4-phenylphenyl)-tropane;(1R,2R,3S)-2-Carbomethoxy-3-(4-t-butyl-phenyl)-tropane;(1R,2R,3S)-2-(4-Fluoro-benzoyl)-3-(4-fluorophenyl)-tropane;(1S,2S,4S,7R)-2-(3,4-Dichlorophenyl)-8-azatricyclo[5.4.0.0^(4,8)]undecan-11-one;(1S,2S,4S,7R)-2-(3,4-Dichlorophenyl)-8-azatricyclo[5.4.0.0^(4,8)]undecan-11-ol;(1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]decan-5-one;(1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]decan-5-oneO-methyl-oxime;(1S,2S,4S,7R)-2-(4-Chlorophenyl)-8-azatricyclo[5.4.0.0^(4,8)]undecan-11-one;(1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0⁴]decan-5-ol;(1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]dec-5-ylacetate;(1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]dec-5-ylmethane sulphate;(1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-5-methoxy-7-azatricyclo[5.3.0.0^(4,8)]decane;(1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-5-ethoxy-7-azatricyclo[5.3.0.0.^(4,8)]decane;(1S,3S,4S,8R)-3-(4-chlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]decan-5-one;(1S,3S,4S,8R)-3-(4-chlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]decan-5-ol;(1S,3S,4S,8R)-3-(4-Chlorophenyl)-5-ethoxy-7-azatricyclo[5.3.0.0^(4,8)]decane;(1S,3S,4S,8R)-3-(3,4-Dichlorophrnyl)-7-azatricyclo[5.3.0.0^(4,8)]decan-5-oneO-benzyl-oxime;(1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]decan-5-oneO-allyl-oxime;(1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]decan-5-oneoxime; (1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]decan-5-one O-tert.-butyl-oxime;(1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]decan-5-one O-ethyl-oxime;(1S,3S,4S,8R)-5-Allyloxy-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]decane;Ethyl (1S,3S,4S,8R)-2-[3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]dec-5-yliden]acetate;(1S,3S,4S,8R)-3-(4-Chlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]decan-5-oneoxime;N1-[1S,3S,4S,8R)-3-(4-Chlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]dec-5-yl]acetamide;(1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0^(4,8)]dec-5-ylamine; or a pharmaceutically acceptable addition salt thereof.
 7. Themethod according to claim 1, wherein the disease to be treated,prevented or alleviated is an ischemic disease, an anoxic episode, or aninjury to the brain and other parts of the CNS caused by trauma or otherinjury, such as a blow to the head.
 8. The method according to claim 1,wherein the disease to be treated, prevented or alleviated is selectedfrom an cerebrovascular disorder such as cerebral ischemia or cerebralinfarction resulting from such as tromboembolic or haemorrhagic stroke,cerebral vasospasm, hypoglycaemia, cardiac arrest, perinatal asphyxia,anoxia such as from near-drowning, pulmonary surgery or cerebral trauma.9. The method according to claim 1, wherein the disease to be treated,prevented or alleviated is selected from brain damage following orcaused by: cerebral ischemia, cardiac arrest, high-risk surgery such ascardiac surgery, stroke, neonatal hypoxia, hypoxia caused by compromisedlung function, neonatal anoxia, anoxia caused by compromised lungfunction, cerebral trauma, secondary regional ischemia induced by brainoedema, increased intercranial pressure, open brain surgery,endarterectomy, surgical interventions involving temporary, artificiallysustained arrest of cardiopulmonary functions resulting in impairment ofcerebral blood flow, or emergency treatment involving cardiopulmonaryresuscitation (CPR).
 10. (Canceled)